Fused thiazole derivatives as kinase inhibitors

ABSTRACT

A series of 6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5H)-one derivatives, which are substituted in the 2-position by a substituted morpholin-4-yl moiety, being selective inhibitors of PI3 kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.

This application is a continuation of U.S. application Ser. No.12/666,481 filed Sep. 22, 2010, and issued as U.S. Pat. No. 8,338,592 onDec. 25, 2012, which claims priority from International Application No.PCT/GB2008/002194 filed Jun. 24, 2008, which claims the benefit ofInternational Application No. PCT/GB2007/002390 filed Jun. 26, 2007, thedisclosures of which are incorporated herein by reference.

The present invention relates to a class of fused thiazole derivatives,and to their use in therapy. More particularly, the invention provides afamily of 6,7-dihydro-[1,3]thiazolo[5,4-c]pyridin-4(5H)-one derivatives,which are substituted in the 2-position by a substituted morpholin-4-ylmoiety. These compounds are selective inhibitors of phosphoinositide3-kinase (PI3K) enzymes, and are accordingly of benefit aspharmaceutical agents, especially in the treatment of adverseinflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic,oncological, nociceptive and ophthalmic conditions.

The PI3K pathway is implicated in a variety of physiological andpathological functions that are believed to be operative in a range ofhuman diseases. Thus, PI3Ks provide a critical signal for cellproliferation, cell survival, membrane trafficking, glucose transport,neurite outgrowth, membrane ruffling, superoxide production, actinreorganization and chemotaxis (cf. S. Ward et al., Chemistry & Biology,2003, 10, 207-213; and S. G. Ward & P. Finan, Current Opinion inPharmacology, 2003, 3, 426-434); and are known to be involved in thepathology of cancer, and metabolic, inflammatory and cardiovasculardiseases (cf. M. P. Wymann et al., Trends in Pharmacol. Sci., 2003, 24,366-376). Aberrant upregulation of the PI3K pathway is implicated in awide variety of human cancers (cf. S. Brader & S. A. Eccles, Tumori,2004, 90, 2-8).

The compounds in accordance with the present invention, being potent andselective PI3K inhibitors, are therefore beneficial in the treatmentand/or prevention of various human ailments. These include autoimmuneand inflammatory disorders such as rheumatoid arthritis, multiplesclerosis, asthma, inflammatory bowel disease, psoriasis and transplantrejection; cardiovascular disorders including thrombosis, cardiachypertrophy, hypertension, and irregular contractility of the heart(e.g. during heart failure); neurodegenerative disorders such asAlzheimer's disease, Parkinson's disease, Huntington's disease, stroke,amyotrophic lateral sclerosis, spinal cord injury; head trauma andseizures; metabolic disorders such as obesity and type 2 diabetes;oncological conditions including leukaemia, glioblastoma, lymphoma,melanoma, and human cancers of the liver, bone, skin, brain, pancreas,lung, breast, stomach, colon, rectum, prostate, ovary and cervix; painand nociceptive disorders; and ophthalmic disorders includingage-related macular degeneration (ARMD).

In addition, the compounds in accordance with the present invention maybe beneficial as pharmacological standards for use in the development ofnew biological tests and in the search for new pharmacological agents.Thus, the compounds of this invention may be useful as radioligands inassays for detecting compounds capable of binding to human PI3K enzymes.

WO 2006/114606 describes fused bicyclic thiazole derivatives asselective inhibitors of PI3 kinase enzymes which are accordingly ofbenefit in medicine, for example in the treatment of inflammatory,autoimmune, cardiovascular, neurodegenerative, metabolic, oncological,nociceptive and ophthalmic conditions.

Various fused thiazole derivatives are disclosed in Liebigs Annalen derChemie, 1986, 780-784; and in Russian Journal of General Chemistry(translation of Zhurnal Obshchei Khimii), 2000, 70[5], 784-787. However,none of the compounds disclosed in either of those publicationscorresponds to a compound of the present invention; and no therapeuticutility is ascribed to any of the compounds disclosed therein.

The compounds in accordance with the present invention are potent andselective PI3K inhibitors having a binding affinity (IC₅₀) for the humanPI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ isoform of 50 μM or less,generally of 20 μM or less, usually of 5 μM or less, typically of 1 μMor less, suitably of 500 nM or less, ideally of 100 nM or less, andpreferably of 20 nM or less (the skilled person will appreciate that alower IC₅₀ figure denotes a more active compound). The compounds of theinvention may possess at least a 10-fold selective affinity, typicallyat least a 20-fold selective affinity, suitably at least a 50-foldselective affinity, and ideally at least a 100-fold selective affinity,for the human PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ isoformrelative to other human kinases.

The compounds of the invention possess notable advantages in terms oftheir high potency and selectivity, demonstrable efficacy, and valuablepharmacokinetic properties (including clearance and bioavailability).

The present invention provides a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof:

wherein

R¹¹ represents hydrogen or C₁₋₆ alkyl; and

R¹² represents hydrogen; or C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl,C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, C₃₋₇heterocycloalkyl, C₃₋₇ heterocycloalkyl-(C₁₋₆)alkyl, heteroaryl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substitutedby one or more substituents; or

R¹¹ and R¹², when taken together with the carbon atom to which they areboth attached, represent C₃₋₇ cycloalkyl or C₃₋₇ heterocycloalkyl,either of which groups may be optionally substituted by one or moresubstituents;

T represents oxygen or N—R²⁵;

V represents carbon or nitrogen;

W represents carbon or nitrogen;

R²³ represents hydrogen, halogen, cyano, nitro, C₁₋₆ alkyl,hydroxy(C₁₋₆)alkyl, trifluoromethyl, aryl(C₁₋₆)alkyl, oxazolinyl,triazolyl, hydroxy, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy, C₃₋₇cycloalkoxy, C₃₋₇ cycloalkyl(C₁₋₆)alkoxy, morpholinyl(C₁₋₆)alkoxy,aryloxy, aryl(C₁₋₆)alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl,arylsulphinyl, arylsulphonyl, C₁₋₆ alkylsulphonyloxy, amino, azetidinyl,morpholinyl, C₂₋₆ alkylcarbonylamino, C₂₋₆ alkylcarbonylaminomethyl,C₂₋₆ alkoxycarbonylamino, [(C₂₋₆)alkoxycarbonyl][(C₁₋₆)alkyl]amino, C₁₋₆alkylsulphonylamino, C₂₋₆ alkylcarbonyl, C₂₋₆ alkylcarbonyl oxime, C₂₋₆alkylcarbonyl O-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C₂₋₆alkoxycarbonyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,[hydroxy(C₁₋₆)-alkyl]aminocarbonyl,[di(C₁₋₆)alkylamino(C₁₋₆)alkyl]aminocarbonyl,di(C₁₋₆)alkylaminocarbonyl,[(C₁₋₆)alkyl][cyano(C₁₋₆)alkyl]aminocarbonyl,[(C₁₋₆)alkyl][hydroxy(C₁₋₆)-alkyl]aminocarbonyl,[(C₁₋₆)alkoxy(C₁₋₆)alkyl][(C₁₋₆)alkyl]aminocarbonyl,[di(C₁₋₆)alkyl-amino(C₁₋₆)alkyl][(C₁₋₆)alkyl]aminocarbonyl, C₃₋₇cycloalkyl(C₁₋₆)alkylaminocarbonyl, aryl(C₁₋₆)alkylaminocarbonyl,heteroarylaminocarbonyl, heteroaryl(C₁₋₆)alkylaminocarbonyl,azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl,C₂₋₆ alkoxycarbonylaminoazetidinylcarbonyl, pyrrolidinylcarbonyl,(C₁₋₆)alkylpyrrolidinylcarbonyl, C₁₋₆alkoxy(C₁₋₆)alkylpyrrolidinylcarbonyl,di(C₁₋₆)alkylaminopyrrolidinyl-carbonyl, thiazolidinylcarbonyl,oxothiazolidinylcarbonyl, piperidinylcarbonyl,(C₁₋₆)-alkylpiperazinylcarbonyl, morpholinylcarbonyl, C₁₋₆alkylsulphonyl, C₁₋₆ alkylsulphonyl-methyl ordi(C₁₋₆)alkylaminosulphonyl; and

R²⁴ represents hydrogen, halogen, C₁₋₆ alkoxy ordi(C₁₋₆)alkylaminocarbonyl; or

R²³ and R²⁴, when situated on adjacent carbon atoms, together representmethylenedioxy or difluoromethylenedioxy; and

R²⁵ represents C₁₋₆ alkyl.

Where any of the groups in the compounds of formula (I) above is statedto be optionally substituted, this group may be unsubstituted, orsubstituted by one or more substituents. Typically, such groups will beunsubstituted, or substituted by one or two substitutents. Suitably,such groups will be unsubstituted or monosubstituted.

For use in medicine, the salts of the compounds of formula (I) will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds of the invention or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundof the invention with a solution of a pharmaceutically acceptable acidsuch as hydrochloric acid, sulphuric acid, methanesulphonic acid,fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid,citric acid, tartaric acid or phosphoric acid. Furthermore, where thecompounds of the invention carry an acidic moiety, e.g. carboxy,suitable pharmaceutically acceptable salts thereof may include alkalimetal salts, e.g. sodium or potassium salts; alkaline earth metal salts,e.g. calcium or magnesium salts; and salts formed with suitable organicligands, e.g. quaternary ammonium salts.

The present invention includes within its scope solvates of thecompounds of formula (I) above. Such solvates may be formed with commonorganic solvents, e.g. hydrocarbon solvents such as benzene or toluene;chlorinated solvents such as chloroform or dichloromethane; alcoholicsolvents such as methanol, ethanol or isopropanol; ethereal solventssuch as diethyl ether or tetrahydrofuran; or ester solvents such asethyl acetate. Alternatively, the solvates of the compounds of formula(I) may be formed with water, in which case they will be hydrates.

Suitable alkyl groups which may be present on the compounds of theinvention include straight-chained and branched C₁₋₆ alkyl groups, forexample C₁₋₄ alkyl groups. Typical examples include methyl and ethylgroups, and straight-chained or branched propyl, butyl and pentylgroups. Particular alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyland 3-methylbutyl. Derived expressions such as “C₁₋₆ alkoxy”, “C₁₋₆alkylthio”, “C₁₋₆ alkylsulphonyl” and “C₁₋₆ alkylamino” are to beconstrued accordingly.

Specific C₃₋₇ cycloalkyl groups are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

Suitable aryl(C₁₋₆)alkyl groups include benzyl, phenylethyl,phenylpropyl and naphthylmethyl.

Suitable heterocycloalkyl groups, which may comprise benzo-fusedanalogues thereof, include azetidinyl, tetrahydrofuranyl,dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl,imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,piperazinyl, 1,2,3,4-tetrahydro-quinoxalinyl, homopiperazinyl,morpholinyl, benzoxazinyl and thiomorpholinyl.

Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl,thienyl, benzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[3,2-c]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, indazolyl,oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl,isothiazolyl, imidazolyl, benzimidazolyl, imidazo[1,2-a]pyridinyl,imidazo[4,5-b]pyridinyl, imidazo[1,2-c]pyrimidinyl,imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl,benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl,pyridazinyl, cinnolinyl, pyrimidinyl, pyrazinyl, quinoxalinyl andchromenyl groups.

The term “halogen” as used herein is intended to include fluorine,chlorine, bromine and iodine atoms, especially fluoro or chloro.

Where the compounds of formula (I) have one or more asymmetric centres,they may accordingly exist as enantiomers. Where the compounds of theinvention possess two or more asymmetric centres, they may additionallyexist as diastereomers. The invention is to be understood to extend toall such enantiomers and diastereomers, and to mixtures thereof in anyproportion, including racemates. Formula (I) and the formulae depictedhereinafter are intended to represent all individual stereoisomers andall possible mixtures thereof, unless stated or shown otherwise. Inaddition, compounds of formula (I) may exist as tautomers, for exampleketo (CH₂C═O)-enol (CH═CHOH) tautomers. Formula (I) and the formulaedepicted hereinafter are intended to represent all individual tautomersand all possible mixtures thereof, unless stated or shown otherwise.

Typical values of R¹¹ include hydrogen, methyl and ethyl. In oneembodiment, R¹¹ is hydrogen. In another embodiment, R¹¹ is C₁₋₆ alkyl,especially methyl.

Suitably, R¹² represents hydrogen; or C₁₋₆ alkyl, C₃₋₇ cycloalkyl oraryl, any of which groups may be optionally substituted by one or moresubstituents.

Examples of typical substituents on R¹² include halogen, cyano, nitro,C₁₋₆ alkyl, trifluoromethyl, hydroxy, C₁₋₆ alkoxy, difluoromethoxy,trifluoromethoxy, aryloxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl, amino,C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino, C₂₋₆alkoxycarbonylamino, C₁₋₆ alkylsulphonylamino, formyl, C₂₋₆alkylcarbonyl, carboxy, C₂₋₆ alkoxycarbonyl, aminocarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl, C₁₋₆alkylaminosulphonyl and di(C₁₋₆)alkylaminosulphonyl; especially halogen,C₁₋₆ alkoxy or C₁₋₆ alkylthio.

Examples of particular substituents on R¹² include fluoro, chloro,bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy,difluoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl,amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino,methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl,aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl;especially chloro, methoxy or methylthio.

Typical values of R¹² include hydrogen, methyl, n-propyl, isopropyl,isobutyl, cyclohexyl and phenyl. A particular value of R¹² is methyl.

Alternatively, R¹¹ and R¹² may together form an optionally substitutedspiro linkage. Thus, R¹¹ and R¹², when taken together with the carbonatom to which they are both attached, may represent C₃₋₇ cycloalkyl orC₃₋₇ heterocycloalkyl, either of which groups may be unsubstituted, orsubstituted by one or more, typically by one or two, substituents. Inthis context, R¹¹ and R¹², when taken together with the carbon atom towhich they are both attached, may suitably represent an optionallysubstituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring.

In a preferred embodiment, T is N—R²⁵. In another embodiment, T isoxygen.

In a preferred embodiment, V is carbon. In another embodiment, V isnitrogen.

In a preferred embodiment, W is carbon. In another embodiment, W isnitrogen.

The present invention also provides a compound of formula (I) asdepicted above, or a pharmaceutically acceptable salt or solvatethereof, wherein R²³ represents hydrogen, halogen, cyano, nitro, C₁₋₆alkyl, hydroxy(C₁₋₆)alkyl, trifluoromethyl, aryl(C₁₋₆)alkyl, hydroxy,C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy,aryl(C₁₋₆)alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, arylsulphinyl,arylsulphonyl, C₁₋₆ alkylsulphonyloxy, amino, C₂₋₆ alkylcarbonylamino,C₁₋₆ alkylsulphonylamino, C₂₋₆ alkylcarbonyl, carboxy, C₂₋₆alkoxycarbonyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,[hydroxy(C₁₋₆)alkyl]aminocarbonyl, di(C₁₋₆)alkylaminocarbonyl,[(C₁₋₆)alkyl][hydroxy(C₁₋₆)alkyl]aminocarbonyl,aryl(C₁₋₆)alkylaminocarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl,piperidinylcarbonyl, (C₁₋₆)alkylpiperazinylcarbonyl ormorpholinylcarbonyl.

The present invention further provides a compound of formula (I) asdepicted above, or a pharmaceutically acceptable salt or solvatethereof, wherein R²³ represents hydrogen, halogen, cyano, C₁₋₆ alkyl,hydroxy(C₁₋₆)alkyl, trifluoromethyl, aryl(C₁₋₆)alkyl, hydroxy, C₁₋₆alkoxy, trifluoromethoxy, aryloxy, aryl(C₁₋₆)alkoxy, C₁₋₆ alkylthio,C₁₋₆ alkylsulphinyl, arylsulphinyl, arylsulphonyl, C₁₋₆alkylsulphonyloxy, amino, C₂₋₆ alkylcarbonylamino, C₁₋₆alkylsulphonylamino, C₂₋₆ alkylcarbonyl or aminocarbonyl.

Particular values of R²³ include hydrogen, halogen, cyano, nitro,oxazolinyl, triazolyl, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy,C₃₋₇ cycloalkoxy, C₃₋₇ cycloalkyl(C₁₋₆)alkoxy, morpholinyl(C₁₋₆)alkoxy,azetidinyl, morpholinyl, C₂₋₆ alkylcarbonylamino, C₂₋₆alkylcarbonylaminomethyl, C₂₋₆ alkoxycarbonylamino,[(C₂₋₆)alkoxycarbonyl][(C₁₋₆)alkyl]amino, C₁₋₆ alkylsulphonylamino, C₂₋₆alkylcarbonyl, C₂₋₆ alkylcarbonyl oxime, C₂₋₆ alkylcarbonylO-(methyl)oxime, trifluoromethylcarbonyl, carboxy, C₂₋₆ alkoxycarbonyl,aminocarbonyl, C₁₋₆ alkylaminocarbonyl,[hydroxy(C₁₋₆)-alkyl]aminocarbonyl,[di(C₁₋₆)alkylamino(C₁₋₆)alkyl]aminocarbonyl,di(C₁₋₆)alkylaminocarbonyl,[(C₁₋₆)alkyl][cyano(C₁₋₆)alkyl]aminocarbonyl,[(C₁₋₆)alkyl][hydroxy(C₁₋₆)-alkyl]aminocarbonyl,[(C₁₋₆)alkoxy(C₁₋₆)alkyl][(C₁₋₆)alkyl]aminocarbonyl,[di(C₁₋₆)alkyl-amino(C₁₋₆)alkyl][(C₁₋₆)alkyl]aminocarbonyl, C₃₋₇cycloalkyl(C₁₋₆)alkylaminocarbonyl, aryl(C₁₋₆)alkylaminocarbonyl,heteroarylaminocarbonyl, heteroaryl(C₁₋₆)alkylaminocarbonyl,azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl,C₂₋₆ alkoxycarbonylatninoazetidinylcarbonyl, pyrrolidinylcarbonyl,(C₁₋₆)alkylpyrrolidinylcarbonyl, C₁₋₆alkoxy(C₁₋₆)alkylpyrrolidinylcarbonyl,di(C₁₋₆)alkylaminopyrrolidinyl-carbonyl, thiazolidinylcarbonyl,oxothiazolidinylcarbonyl, piperidinylcarbonyl,(C₁₋₆)-alkylpiperazinylcarbonyl, morpholinylcarbonyl, C₁₋₆alkylsulphonyl, C₁₋₆ alkylsulphonyl-methyl anddi(C₁₋₆)alkylaminosulphonyl.

Typical values of R²³ include hydrogen, halogen, nitro, difluoromethoxy,trifluoromethoxy, carboxy, C₂₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,[hydroxy-(C₁₋₆)alkyl]aminocarbonyl, di(C₁₋₆)alkylaminocarbonyl,[(C₁₋₆)alkyl][hydroxy(C₁₋₆)alkyl]-aminocarbonyl,aryl(C₁₋₆)alkylaminocarbonyl, azetidinylcarbonyl, piperidinylcarbonyl,(C₁₋₆)alkylpiperazinylcarbonyl and morpholinylcarbonyl.

Suitable values of R²³ include hydrogen, C₁₋₆ alkyl, hydroxy,aryl(C₁₋₆)alkoxy and C₁₋₆ alkylsulphonyloxy.

Illustrative values of R²³ include hydrogen, fluoro, chloro, bromo,cyano, nitro, methyl, hydroxymethyl, trifluoromethyl, benzyl, hydroxy,methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, phenoxy, benzyloxy,methylthio, methylsulphinyl, phenylsulphinyl, phenylsulphonyl,methylsulphonyloxy, amino, acetylamino, methylsulphonylamino, acetyl,carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,(hydroxyethyl)aminocarbonyl, dimethylaminocarbonyl, N-(hydroxyethyl)-N-methylaminocarbonyl, benzylaminocarbonyl, azetidinylcarbonyl,pyrrolidinylcarbonyl, piperidinylcarbonyl, methylpiperazinylcarbonyl andmorpholinylcarbonyl.

Specific values of R²³ include hydrogen, fluoro, chloro, bromo, cyano,methyl, hydroxymethyl, trifluoromethyl, benzyl, hydroxy, methoxy,ethoxy, trifluoromethoxy, phenoxy, benzyloxy, methylthio,methylsulphinyl, phenylsulphinyl, phenylsulphonyl, methylsulphonyloxy,amino, acetylamino, methylsulphonylamino, acetyl and aminocarbonyl;especially hydrogen, methyl, hydroxy, benzyloxy or methylsulphonyloxy.

Definitive values of R²³ include hydrogen, fluoro, chloro, cyano, nitro,oxazolinyl, triazolyl, methoxy, difluoromethoxy, trifluoromethoxy,cyclobutyloxy, cyclopropyl-methoxy, morpholinylethoxy, azetidinyl,morpholinyl, acetylamino, acetylaminomethyl, methoxycarbonylamino,N-methoxycarbonyl-N-methylamino, methylsulphonylamino, acetyl, acetyloxime, acetyl O-(methyl)oxime, trifluoromethylcarbonyl, carboxy,methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,(hydroxyethyl)aminocarbonyl, (dimethylaminoethyl)aminocarbonyl,(1-hydroxyprop-2-yl)aminocarbonyl, dimethylaminocarbonyl,N-(cyanomethyl)-N-methylaminocarbonyl,N-(cyanoethyl)-N-methylaminocarbonyl,N-(hydroxyethyl)-N-methylaminocarbonyl,N-(methoxyethyl)-N-methylaminocarbonyl,N-(dimethylaminoethyl)-N-methylaminocarbonyl,N-isopropyl-N-methylaminocarbonyl, diethylaminocarbonyl,cyclopropylmethylaminocarbonyl, benzylaminocarbonyl,pyrazolylaminocarbonyl, pyridinylmethylaminocarbonyl,azetidinylcarbonyl, hydroxyazetidinylcarbonyl, aminoazetidinylcarbonyl,tert-butoxycarbonylamino-azetidinylcarbonyl, pyrrolidinylcarbonyl,methylpyrrolidinylcarbonyl, methoxymethyl-pyrrolidinylcarbonyl,dimethylaminopyrrolidinylcarbonyl, thiazolidinylcarbonyl,oxothiazolidinylcarbonyl, piperidinylcarbonyl,methylpiperazinylcarbonyl, morpholinylcarbonyl, methylsulphonyl,methylsulphonylmethyl and dimethylaminosulphonyl.

Selected values of R²³ include hydrogen, fluoro, nitro, difluoromethoxy,trifluoromethoxy, carboxy, methoxycarbonyl, methylaminocarbonyl,(hydroxyethyl)-aminocarbonyl, dimethylaminocarbonyl,N-(hydroxyethyl)-N-methylaminocarbonyl, benzylaminocarbonyl,azetidinylcarbonyl, piperidinylcarbonyl, methylpiperazinylcarbonyl andmorpholinylcarbonyl.

Typically, R²³ may represent hydrogen, cyano, carboxy, C₂₋₆alkoxycarbonyl, di(C₁₋₆)alkylaminocarbonyl,[(C₁₋₆)alkyl][cyano(C₁₋₆)alkyl]aminocarbonyl,[(C₁₋₆)alkoxy-(C₁₋₆)alkyl][(C₁₋₆)alkyl]aminocarbonyl orazetidinylcarbonyl.

Suitably, R²³ may represent hydrogen, cyano, carboxy, methoxycarbonyl,dimethylaminocarbonyl, N-(cyanomethyl)-N-methylaminocarbonyl,N-(methoxyethyl)-N-methylaminocarbonyl or azetidinylcarbonyl.

A particular value of R²³ is hydrogen. Another value of R²³ is cyano.Another value of R²³ is carboxy. Another value of R²³ is C₂₋₆alkoxycarbonyl, especially methoxycarbonyl. A further value of R²³ isdi(C₁₋₆)alkylaminocarbonyl, especially dimethylaminocarbonyl. A furthervalue of R²³ is [(C₁₋₆)alkyl][cyano(C₁₋₆)alkyl]aminocarbonyl, especiallyN-(cyanomethyl)-N-methylaminocarbonyl. A still further value of R²³ is[(C₁₋₆)alkoxy(C₁₋₆)alkyl][(C₁₋₆)alkyl]aminocarbonyl, especiallyN-(methoxyethyl)-N-methylaminocarbonyl. An additional value of R²³ isazetidinylcarbonyl.

Definitive values of R²⁴ include hydrogen, chloro, methoxy anddimethylaminocarbonyl. A particular value of R²⁴ is hydrogen.

In one embodiment, R²⁵ is suitably methyl.

Specific novel compounds in accordance with the present inventioninclude each of the compounds whose preparation is described in theaccompanying Examples, and pharmaceutically acceptable salts andsolvates thereof.

The present invention also provides a pharmaceutical composition whichcomprises a compound in accordance with the invention as describedabove, or a pharmaceutically acceptable salt or solvate thereof, inassociation with one or more pharmaceutically acceptable carriers.

Pharmaceutical compositions according to the invention may take a formsuitable for oral, buccal, parenteral, nasal, topical, ophthalmic orrectal administration, or a form suitable for administration byinhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methyl cellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogenphosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles or preservatives. Thepreparations may also contain buffer salts, flavouring agents, colouringagents or sweetening agents, as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formula (I) may be formulated for parenteraladministration by injection, e.g. by bolus injection or infusion.Formulations for injection may be presented in unit dosage form, e.g. inglass ampoules or multi-dose containers, e.g. glass vials. Thecompositions for injection may take such forms as suspensions, solutionsor emulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising, preserving and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds offormula (I) may also be formulated as a depot preparation. Suchlong-acting formulations may be administered by implantation or byintramuscular injection.

For nasal administration or administration by inhalation, the compoundsaccording to the present invention may be conveniently delivered in theform of an aerosol spray presentation for pressurised packs or anebuliser, with the use of a suitable propellant, e.g.dichlorodifluoromethane, fluorotrichloromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack or dispensing device may be accompanied byinstructions for administration.

For topical administration the compounds according to the presentinvention may be conveniently formulated in a suitable ointmentcontaining the active component suspended or dissolved in one or morepharmaceutically acceptable carriers. Particular carriers include, forexample, mineral oil, liquid petroleum, propylene glycol,polyoxyethylene, polyoxypropylene, emulsifying wax and water.Alternatively, the compounds according to the present invention may beformulated in a suitable lotion containing the active componentsuspended or dissolved in one or more pharmaceutically acceptablecarriers. Particular carriers include, for example, mineral oil,sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearylalcohol, benzyl alcohol, 2-octyldodecanol and water.

For ophthalmic administration the compounds according to the presentinvention may be conveniently formulated as microionized suspensions inisotonic, pH-adjusted sterile saline, either with or without apreservative such as a bactericidal or fungicidal agent, for examplephenylmercuric nitrate, benzylalkonium chloride or chlorhexidineacetate. Alternatively, for ophthalmic administration compounds may beformulated in an ointment such as petrolatum.

For rectal administration the compounds according to the presentinvention may be conveniently formulated as suppositories. These can beprepared by mixing the active component with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and so will melt in the rectum to release the activecomponent. Such materials include, for example, cocoa butter, beeswaxand polyethylene glycols.

The quantity of a compound of the invention required for the prophylaxisor treatment of a particular condition will vary depending on thecompound chosen and the condition of the patient to be treated. Ingeneral, however, daily dosages may range from around 10 ng/kg to 1000mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to40 mg/kg body weight, for oral or buccal administration, from around 10ng/kg to 50 mg/kg body weight for parenteral administration, and fromaround 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000mg, for nasal administration or administration by inhalation orinsufflation.

The compounds of formula (I) above may be prepared by a process whichcomprises reacting a compound of formula (II) with a compound of formula(III):

wherein R¹¹, R¹², T, V, W, R²³ and R²⁴ are as defined above, and L¹represents a suitable leaving group.

The leaving group L¹ is typically a halogen atom, e.g. bromo.

The reaction is conveniently effected at an elevated temperature in asuitable solvent, e.g. a lower alkanol such as isopropanol or a cyclicether such as tetrahydrofuran, typically under basic conditions, e.g. inthe presence of an organic base such as N,N-diisopropylethylamine or2,6-lutidine.

Alternatively, the reaction may be effected at an elevated temperaturein a solvent such as 2-ethoxyethanol in the presence of a catalyticquantity of a mineral acid, e.g. concentrated hydrochloric acid.

In another alternative, the reaction may be effected at an elevatedtemperature in a suitable solvent, e.g. a cyclic ether such astetrahydrofuran, or an aromatic solvent such as toluene, typically underbasic conditions, e.g. in the presence of an inorganic base such assodium tert-butoxide, in the presence of a transition metal catalyst.The transition metal catalyst is suitably palladium(II) acetate, inwhich case the reaction will ideally be performed in the presence oftert-butylphosphonium tetrafluoroborate or dicyclohexyldiphenylphosphine.

The intermediates of formula (II) above wherein L¹ is bromo may beprepared from a compound of formula (IV):

wherein R¹¹ and R¹² are as defined above; by diazotization/bromination.

The reaction is conveniently effected by stirring compound (IV) withtert-butyl nitrite and copper(II) bromide in a suitable solvent, e.g.acetonitrile.

The intermediates of formula (IV) above may be prepared by reactingthiourea with a compound of formula (V):

wherein R¹¹ and R¹² are as defined above, and L² represents a suitableleaving group.

The leaving group L² is typically a halogen atom, e.g. bromo.

The reaction is conveniently effected at an elevated temperature in asuitable solvent, e.g. a cyclic ether such as tetrahydrofuran, typicallyunder basic conditions, e.g. in the presence of an organic base such asN,N-diisopropylethylamine.

Alternatively, the reaction may be accomplished by heating the reactantsin a lower alkanol solvent, e.g. a C₁₋₆ alkyl alcohol such as ethanol.

In another procedure, the compounds of formula (I) may be prepared by aprocess which comprises reacting a compound of formula (V) as definedabove with a compound of formula (VI):

wherein T, V, W, R²³ and R²⁴ are as defined above; under conditionsanalogous to those described above for the reaction between thiourea andcompound (V).

In an additional procedure, the compounds of formula (I) wherein T isoxygen may be prepared by a process which comprises reacting a compoundof formula (VII) with a compound of formula (VIII):

wherein R¹¹, R¹², V, W, R²³ and R²⁴ are as defined above; in thepresence of a transition metal catalyst; followed by removal of thetrimethylsilyl moiety from the 2-position of the resulting cycloadditionproduct.

The transition metal catalyst of use in the reaction between compounds(VII) and (VIII) is suitably palladium(II) acetate, in which case thereaction may conveniently be effected at an elevated temperature in asuitable solvent, e.g. a dipolar aprotic solvent such asN,N-dimethylformamide, in the presence of lithium chloride and a base,typically an inorganic base, e.g. an alkaline earth metal carbonate suchas sodium carbonate.

Removal of the trimethylsilyl moiety from the resulting cycloadditionproduct may be effected by treatment with an acid, e.g. a mineral acidsuch as hydrochloric acid.

Alternatively, the trimethylsilyl moiety may be removed by treatmentwith a base, typically an inorganic base, e.g. an alkali metal hydroxidesuch as lithium hydroxide.

The intermediates of formula (VII) above may be prepared by reacting acompound of formula (V) as defined above with the compound of formula(IX):

under conditions analogous to those described above for the reactionbetween compounds (V) and (VI).

Where they are not commercially available, the starting materials offormula (III), (V), (VI), (VIII) and (IX) may be prepared by methodsanalogous to those described in the accompanying Examples, or bystandard methods well known from the art.

It will be understood that any compound of formula (I) initiallyobtained from any of the above processes may, where appropriate,subsequently be elaborated into a further compound of formula (I) bytechniques known from the art. By way of example, a compound of formula(I) wherein R²³ represents C₂₋₆ alkoxycarbonyl, e.g. methoxycarbonyl,may be converted into the corresponding compound wherein R²³ representscarboxy (—CO₂H) under standard saponification conditions, e.g. bytreatment with a base such as lithium hydroxide. A compound of formula(I) wherein R²³ represents carboxy (—CO₂H) may be converted into thecorresponding compound wherein R²³ contains an amido group, e.g.methylaminocarbonyl, 2-hydroxyethylaminocarbonyl, dimethylaminocarbonyl,N-(cyanomethyl)-N-methylaminocarbonyl,N-(2-hydroxyethyl)-N-methylaminocarbonyl,N-(2-methoxyethyl)-N-methylaminocarbonyl, benzylaminocarbonyl,azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,4-methylpiperazin-1-ylcarbonyl or morpholin-4-ylcarbonyl, by a two-stageprocedure which comprises (i) treatment of the carboxy derivative withpentafluorophenol in the presence of a condensing agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; and (ii) reaction of thepentafluorophenyl ester thereby obtained with the appropriate amine,e.g. methylamine, 2-hydroxyethylamine, dimethylamine,N-(cyanomethyl)-N-methylamine, N-(2-hydroxyethyl)-N-methylamine,N-(2-methoxyethyl)-N-methylamine, benzylamine, azetidine, pyrrolidine,piperidine, 1-methylpiperazine or morpholine.

Where a mixture of products is obtained from any of the processesdescribed above for the preparation of compounds according to theinvention, the desired product can be separated therefrom at anappropriate stage by conventional methods such as preparative HPLC; orcolumn chromatography utilising, for example, silica and/or alumina inconjunction with an appropriate solvent system.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques. In particular,where it is desired to obtain a particular enantiomer of a compound offormula (I) this may be produced from a corresponding mixture ofenantiomers using any suitable conventional procedure for resolvingenantiomers. Thus, for example, diastereomeric derivatives, e.g. salts,may be produced by reaction of a mixture of enantiomers of formula (I),e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base.The diastereomers may then be separated by any convenient means, forexample by crystallisation, and the desired enantiomer recovered, e.g.by treatment with an acid in the instance where the diastereomer is asalt. In another resolution process a racemate of formula (I) may beseparated using chiral HPLC. Moreover, if desired, a particularenantiomer may be obtained by using an appropriate chiral intermediatein one of the processes described above. Alternatively, a particularenantiomer may be obtained by performing an enantiomer-specificenzymatic biotransformation, e.g. an ester hydrolysis using an esterase,and then purifying only the enantiomerically pure hydrolysed acid fromthe unreacted ester antipode. Chromatography, recrystallisation andother conventional separation procedures may also be used withintermediates or final products where it is desired to obtain aparticular geometric isomer of the invention.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 3^(rd) edition, 1999. The protecting groups may be removedat any convenient subsequent stage utilising methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds in accordance with this invention potently inhibit theactivity of human PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ.

Enzyme Inhibition Assays

Measurement of the ability of compounds to inhibit the lipid kinaseactivity of the four class 1 PI3 kinase isoforms (α, β, γ and δ) wasperformed using a commercially available homogeneous time-resolvedfluorescence assay as described by Gray et al., Anal. Biochem., 2003,313, 234-245, according to the manufacturer's instructions (Upstate).All assays were performed at 2 μM ATP and a concentration of purifiedclass 1 PI3 kinase known to generate product within the linear range ofthe assay. Dilutions of inhibitor in DMSO were added to the assay andcompared with assays run in the presence of 2% (v/v) DMSO alone (100%activity). The concentration of inhibitor required to inhibit the enzymeactivity by 50% is quoted as the IC₅₀.

When tested in the above assay, the compounds of the accompanyingExamples were all found to possess IC₅₀ values for inhibition ofactivity of human PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ of 50 μMor better.

EXAMPLES

Abbreviations DCM: dichloromethane DMF: N,N-dimethylformamide DMSO:dimethylsulphoxide Et: ethyl Et₂O: diethyl ether THF: tetrahydrofuranr.t.: room temperature sat.: saturated MeCN: acetonitrile EtOAc: ethylacetate MeOH: methanol AcOH: acetic acid EtOH: ethanol IPA: isopropylalcohol RT: retention time Me: methyl h: hour conc.: concentrated SiO₂:silica br.: broad w or wt: weight M: mass ^(t)Bu: tert-butyl v: volumeNBS: N-bromosuccinimide brine: saturated aqueous sodium chloridesolution HPLC: High Performance Liquid Chromatography LCMS: LiquidChromatography Mass Spectrometry DIPEA: N,N-diisopropylethylamine ES+:Electrospray Positive Ionisation ES−: Electrospray Negative IonisationEDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride DMPU:1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinoneAnalytical Conditions

All NMRs were obtained either at 300 MHz or 400 MHz.

Compounds were named with the aid of ACD Labs Name (v. 7.0, 9.0 or 10.0)supplied by Advanced Chemical Development, Toronto, Canada.

All reactions involving air- or moisture-sensitive reagents wereperformed under a nitrogen atmosphere using dried solvents andglassware.

Compound purities and retention times were determined by LCMS using oneof the Methods 1-9 below.

Preparative HPLC for compounds that required it was performed using oneof the Methods 10-13 below.

Method 1

Luna C18(2) 100×4.6 mm, 5 μm column. Mobile phase A: 99.92% water, 0.08%formic acid. Mobile phase B: 99.92% MeCN, 0.08% formic acid.

Gradient program (flow rate 3.0 mL/min, column temperature 35° C.):

Time A % B % 0.00 95.0 5.0 4.40 5.0 95.0 5.30 5.0 95.0 5.32 95.0 5.06.50 95.0 5.0

Method 2:

Luna C18(2) 100×4.6 mm, 5 μm column. Mobile phase A: 5 mM NH₄OAc, pH5.8. Mobile phase B: 95:5 MeCN:100 mM NH₄OAc, pH 5.8.

Gradient program (flow rate 3.0 mL/min, column temperature 35° C.):

Time A % B % 0.00 95.0 5.0 4.40 5.0 95.0 5.30 5.0 95.0 5.32 95.0 5.06.50 95.0 5.0

Method 3:

Gemini C18 50×4.6 mm, 5 μm column. Mobile phase A: 99.9% 10 mM ammoniumformate, 0.1% formic acid. Mobile phase B: 94.9% MeCN, 0.1% formic acid,5% mobile phase A.

Gradient program (flow rate 0.9 mL/min, column temperature 40° C.):

Time A % B % 0.00 95.0 5.0 2.00 5.0 95.0 5.50 5.0 95.0

Method 4:

Gemini C18 50×4.6 mm, 5 μm column. Mobile phase A: 99.9% 10 mM ammoniumformate, 0.1% ammonia. Mobile phase B: 94.9% MeCN, 0.1% ammonia, 5%mobile phase A.

Gradient program (flow rate 3.0 mL/min, column temperature 40° C.):

Time A % B % 0.00 95.0 5.0 2.00 5.0 95.0 5.50 5.0 95.0

Method 5:

Gemini C18 50×4.6 mm, 5 μm column. Mobile phase A: 99.9% ammoniumformate, 0.1% formic acid. Mobile phase B: 94.9% MeCN, 0.1% formic acid,5% mobile phase A.

Gradient program (flow rate 0.9 mL/min, column temperature 40° C.):

Time A % B % 0.00 95.0 5.0 2.00 5.0 95.0 4.00 5.0 95.0

Method 6:

Gemini C18 30×3.0 mm, 3 μm column. Mobile phase A: 99.9% 10 mM ammoniumformate, 0.1% formic acid. Mobile phase B: 94.9% MeCN, 0.1% formic acid,5% mobile phase A.

Gradient program (flow rate 1.2 mL/min, column temperature 40° C.):

Time A % B % 0.00 95.0 5.0 4.00 5.0 95.0 5.50 5.0 95.0

Method 7:

Gemini C18 30×3.0 mm, 3 μm column. Mobile phase A: 99.9% 10 mM ammoniumformate, 0.1% ammonia solution. Mobile phase B: 94.9% MeCN, 0.1% ammoniasolution, 5% mobile phase A.

Gradient program (flow rate 1.2 mL/min, column temperature 40° C.):

Time A % B % 0.00 95.0 5.0 4.00 5.0 95.0 5.50 5.0 95.0

Method 8:

Gemini C18 30×3.0 mm, 3 μm column. Mobile phase A: 99.9% 10 mM ammoniumformate, 0.1% formic acid. Mobile phase B: 100% MeCN.

Gradient program (flow rate 1.2 mL/min, column temperature 40° C.):

Time A % B % 0.00 95.0 5.0 2.30 5.0 95.0 3.40 5.0 95.0 3.50 95.0 5.0

Method 9:

Gemini C18 30×3.0 mm, 3 μm column. Mobile phase A: 99.9% 10 mM ammoniumformate, 0.1% ammonia solution. Mobile phase B: 100% MeCN.

Gradient program (flow rate 1.2 mL/min, column temperature 40° C.):

Time A % B % 0.00 95.0 5.0 2.30 5.0 95.0 3.40 5.0 95.0 3.50 95.0 5.0

Method 10:

Luna C18(2) 250×21.2 mm, 5 μm column. Mobile phase A: 99.92% water,0.08% formic acid. Mobile phase B: 99.92% MeCN, 0.08% formic acid.

Gradient program (flow rate 25.0 mL/min), column temperature: ambient,variable gradient.

Method 11:

Luna C18(2) 250×21.2 mm, 5 μm column. Mobile phase A: 10 mM NH₄OAc, pH5.8. Mobile phase B: 95% MeCN, 5% 200 mM NH₄OAc, pH 5.8.

Gradient program (flow rate 25.0 mL/min), column temperature: ambient,variable gradient.

Method 12:

Gemini C18 150×21.2 mm, 10 μm column. Mobile phase A: 99.9% ammoniumformate, 0.1% formic acid. Mobile phase B: 94.9% MeCN, 0.1% formic acid,5% mobile phase A.

Gradient program (flow rate 20.0 mL/min), column temperature: ambient,variable gradient.

Method 13:

Gemini C18 150×21.2 mm, 10 μm column. Mobile phase A: 99.9% ammoniumformate, 0.1% ammonia solution. Mobile phase B: 94.9% MeCN, 0.1% ammoniasolution, 5% mobile phase A.

Gradient program (flow rate 20.0 mL/min), column temperature: ambient,variable gradient.

Intermediate 1 Ethyl 3-amino-3-methylbutanoate hydrochloride

To a stirred solution of ethyl 3,3-dimethylacrylate (5.0 g, 39.1 mmol)in EtOH (20 mL) in a Parr® reactor at 0° C. was added liquid NH₃ (ca 20mL). The reactor was sealed and heated to 90° C. for 24 h. The reactionmixture was then cooled to r.t., bubbled with nitrogen to remove theresidual NH₃ and treated with 4M HCl in dioxane (10 mL). The reactionmixture was stirred for 30 minutes at r.t. and then evaporated in vacuoto dryness. The resulting grey paste was triturated with DCM, filteredand dried to give the title compound (5.0 g, 70%) as a grey solid thatwas used without further purification. δ_(H) (CDCl₃) 8.27 (3H, br. s),4.10 (2H, q, J 7.1 Hz), 2.65 (2H, s), 1.26 (6H, s), 1.20 (3H, t, J 7.1Hz).

Intermediate 2 Ethyl3-[(3-ethoxy-3-oxopropanoyl)amino]-3-methylbutanoate

To a stirred suspension of Intermediate 1 (5.0 g, 27.4 mmol) in DCM (40mL) was added NEt₃ (11.1 g, 15.3 mL, 109.6 mmol). The reaction mixturewas then cooled to 0° C. and ethyl malonyl chloride (4.4 g, 3.7 mL, 28.8mmol) was added dropwise. The suspension was stirred at r.t. for 2 hbefore it was diluted with DCM (50 mL) and washed with aqueous 1M HCl(50 mL) and water (2×50 mL). The organics were dried over MgSO₄,filtered and concentrated in vacuo to give the title compound (5.0 g,71%) as an orange oil that was used without further purification. δ_(H)(DMSO-d₆) 7.75 (1H, br. s), 4.15-3.95 (4H, m), 3.14 (2H, s), 2.71 (2H,s), 1.29 (6H, s), 1.21-1.11 (6H, m).

Intermediate 3 6,6-Dimethylpiperidine-2,4-dione

To a stirred solution of NaOEt, prepared in situ from Na (0.53 g, 23.16mmol) in EtOH (30 mL), was added dropwise a solution of Intermediate 2(5.00 g, 19.30 mmol) in toluene (30 mL) and the reaction mixture washeated to 80° C. for 2 h. The solution was then concentrated to ca 10 mLand the residue was dissolved in toluene (30 mL) and extracted withwater (3×30 mL). The combined aqueous layers were acidified to pH 2-3with aqueous 1M HCl and extracted with EtOAc (4×50 mL). The combinedorganic fractions were dried (MgSO₄), filtered and evaporated in vacuoto give a pale yellow solid that was dissolved in MeCN (90 mL)containing 1% water. The solution was heated to reflux for 2 h and thenevaporated in vacuo to dryness. The resulting solid was triturated withdiisopropyl ether, filtered and dried to give the title compound (1.55g, 57%) as a cream solid that was used without further purification.Both the keto and enol forms were observed (ratio 3.6:1 keto/enol).δ_(H) (DMSO-d₆) 10.29 (1H, br. s, enol), 8.14 (1H, br. s, keto), 6.66(1H, s, enol), 4.81 (1H, s, enol), 3.15 (2H, s), 2.51 (2H, s), 1.20 (6H,s, keto), 1.18 (6H, s, enol).

Intermediate 4(3a,R)-Tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide

To a solution of Intermediate 19 (30 g, 257 mmol) dissolved in anhydrousDCM (250 mL) was added pyridine (43.5 mL, 539 mmol) and the solution wascooled to −70° C. (CO₂/IPA bath). Sulphuryl chloride (21.7 mL, 270 mmol)dissolved in anhydrous DCM (200 mL) was added dropwise over 1 h (so asto maintain the reaction temperature below −60° C.). The reaction wasstirred at −70° C. for 2 h and at −10 to −20° C. (MeOH/ice bath) for 2 hbefore being quenched by the addition of water (15 mL) and warming tor.t. The solution was separated and the aqueous fraction extracted withfurther DCM (2×100 mL). The combined organic fractions were washed withwater (15 mL), brine (15 mL), dried (Na₂SO₄), filtered and concentratedin vacuo to give the title compound (24.7 g, 54%) as a yellow oil whichsolidified to an orange sticky solid on standing at r.t. that was usedwithout further purification. δ_(H) (CDCl₃) 4.51 (1H, dd, J 8.1 and J6.4 Hz), 4.23 (1H, dd, J 9.1 and J 8.1 Hz), 3.95 (1H, dd, J 11.6 and J3.4 Hz), 3.84-3.64 (3H, m), 3.54 (1H, dd, J 11.6 and J 7.7 Hz), 3.29(1H, dt, J 12.0 and J 3.4 Hz), 3.06 (1H, m).

Intermediate 5 (3S)-3-(Prop-2-yn-1-yl)morpholine

To a solution of trimethylsilyl acetylene (27.59 mL, 195.25 mmol)dissolved in anhydrous THF (250 mL) at 0° C. was added n-butyllithium(78.1 mL, 201 mmol, 2.5M in hexanes) dropwise over 15 minutes. Afterstirring at this temperature for 40 minutes, a solution of Intermediate4 (11.65 g, 65.083 mmol) dissolved in DMPU (11 mL) was added slowly over15 minutes and the reaction mixture was allowed to warm to r.t. Afterstirring at r.t. for 18 h, the reaction mixture was quenched by theaddition of water (ca 4 mL) and the solvent (not DMPU) was removed invacuo. To the resultant dark oil were added aqueous HCl (10% v/v, 200mL) and MeOH (100 mL) and the reaction mixture was stirred at r.t. for18 h. The solution was then concentrated in vacuo to give the titlecompound (17.059 g, ca 74% yield) as a crude dark oil (containing ca 11mL DMPU) that was used without further purification. δ_(H) (CD₃OD) 3.89(1H, dd, J 11.2 and J 3.1 Hz), 3.76 (1H, dt, J 11.2 and J 2.7 Hz),3.45-3.56 (1H, m), 3.25 (1H, m), 2.89 (3H, m), 2.39 (1H, t, J 2.7 Hz),2.25 (2H, dd, J 6.8 and J 2.7 Hz). Exchangeable proton was not observed.

Intermediate 6 tert-Butyl(3S)-3-(prop-2-yn-1-yl)morpholine-4-carboxylate

To a solution of crude Intermediate 5 (17.059 g, containing 11 mL DMPU),dissolved in anhydrous DCM (300 mL) at 0° C., was added DIPEA (13.04 mL,74.85 mmol) and di-tert-butyl dicarbonate (15.624 g, 71.59 mmol) and thereaction mixture warmed to r.t. After stirring for 18 h, the reactionmixture was washed with brine and the organic fraction was dried usingan Isolute® phase separator cartridge and concentrated in vacuo to givea dark brown oil. Purification by column chromatography (SiO₂, 10:1EtOAc/hexanes) gave the title compound (8.79 g, 59% from Intermediate 4)as a yellow oil. δ_(H) (CD₃OD) 3.95 (1H, m), 3.75 (1H, d, J 14.2 Hz),3.70 (1H, m), 3.58 (1H, m), 3.42 (1H, m), 3.30 (1H, m), 2.95 (1H, m),2.51 (1H, m), 2.37 (1H, m), 2.19 (1H, t, J 2.7 Hz), 1.35 (9H, s).

Intermediate 7 (Method H) tert-Butyl(3S)-3-[3-(trimethylsilyl)prop-2-yn-1-yl]morpholine-4-carboxylate

To a solution of Intermediate 6 (8.05 g, 35.7 mmol) dissolved inanhydrous THF (250 mL) at 0° C. was added n-butyllithium (15.7 mL, 39.3mmol, 2.5 M in hexanes) dropwise over 15 minutes. After stirring for 30minutes, chlorotrimethylsilane was added slowly over 5 minutes and thereaction mixture stirred for 45 minutes and then allowed to warm to r.t.After stirring at r.t. for 18 h, the reaction mixture was quenched bythe addition of water (ca 1 mL) and the solvent was removed in vacuo.The crude mixture was dissolved in DCM and washed with water, theaqueous phase was extracted with further DCM (500 mL) and the combinedorganic fractions were dried using an Isolute® phase separator cartridgeand concentrated in vacuo to give a dark brown oil. Purification bycolumn chromatography (SiO₂, 5-20% EtOAc/hexanes) gave the titlecompound (8.1 g, 76%) as a colourless oil and recovered startingmaterial (1.25 g, 15%). δ_(H) (CD₃OD) 3.91 (1H, m), 3.82 (1H, d, J 11.7Hz), 3.70 (1H, dd, J 3.6 and J 11.4 Hz), 3.58 (1H, dd, J 2.9 and J 13.7Hz), 3.40-3.20 (2H, m), 2.95 (1H, m), 2.60 (1H, dd, J 9.1 and J 16.7Hz), 2.38 (1H, dd, J 6.4 and J 16.7 Hz), 1.35 (9H, s), 0.00 (9H, s).

Intermediate 8 (Method I) tert-Butyl(3S)-3-{[5-(difluoromethoxy)-2-(trimethylsilyl)-1H-indol-3-yl]methyl}morpholine-4-carboxylate

To a solution of Intermediate 7 (0.571 g, 1.93 mmol) dissolved in DMF(23 mL) was added Intermediate 20 (0.55 g, 1.93 mmol), LiCl (0.082 g,1.93 mmol), Na₂CO₃ (0.409 g, 3.86 mmol) and Pd(OAc)₂ (0.017 g, 0.08mmol) and the reaction mixture was degassed under vacuum and then purgedwith nitrogen. The reaction mixture was then heated at 100° C. for 6 h.The crude reaction mixture was cooled to r.t. and the solvent removed invacuo to give a brown oil. Purification by column chromatography (SiO₂,10-30% EtOAc/hexanes; followed by SiO₂, DCM) gave the title compound(0.462 g, 53%) as a yellow oil. LCMS (ES+) 399.0 ((M-^(t)Bu)+H)⁺, RT3.95 minutes (Method 5).

Intermediate 9 (Method J)5-(Difluoromethoxy)-3-[(3S)-morpholin-3-ylmethyl]-1H-indole

To Intermediate 8 (0.285 g, 0.63 mmol) at 0° C. was added 4M HCl in1,4-dioxane (8 mL) and the reaction mixture was stirred at r.t. for 2 h.The reaction mixture was concentrated in vacuo and the crude residue wasdissolved in DCM (25 mL) and washed with aqueous sat. NaHCO₃ solution (5mL). The aqueous fraction was further extracted with DCM (3×20 mL) andthe combined organic fractions were dried (Na₂SO₄), filtered andconcentrated in vacuo to give the title compound (0.197 g, quantitative)as a yellow oil that was used without further purification. LCMS (ES+)283.0 (M+H)⁺, RT 2.27 minutes (Method 5).

Intermediate 10 (Method K)(3S)-3-{[5-(Difluoromethoxy)-1H-indol-3-yl]methyl}morpholine-4-carbothioamide

To a solution of 1,1′-thiocarbonyldiimidazole (0.137 g, 0.77 mmol) inTHF (5 mL) was added Intermediate 9 (0.197 g, 0.70 mmol) dissolved inTHF (5 mL) and the reaction mixture was stirred at r.t. for 18 h. Thereaction mixture was concentrated in vacuo and dissolved in MeCN (7 mL)and aqueous NH₃ (20% v/v, 7 mL) added. The reaction mixture was stirredat 60° C. for 4 h. After cooling to r.t., the reaction mixture wasconcentrated in vacuo to give a yellow oil. The crude material waspurified by column chromatography (SiO₂, 9:10 EtOAc/hexanes) to give thetitle compound (0.106 g, 44%) as a yellow oil. LCMS (ES+) 342.0 (M+H)⁺,RT 2.91 minutes (Method 5).

Intermediate 11 Methyl3-{[(3S)-4-(tert-butoxycarbonyl)morpholin-3-yl]methyl}-2-(trimethylsilyl)-1H-indole-5-carboxylate

The title compound was prepared from methyl 4-amino-3-iodobenzoate andIntermediate 7 according to Method I and was isolated as a yellow stickysolid (59%) after purification by column chromatography (SiO₂, 10-25%EtOAc/hexanes). LCMS (ES+) 392.0 ((M-^(t)Bu)+H)⁺, RT 3.58 minutes(Method 3).

Intermediate 12 Methyl3-[(3S)-morpholin-3-ylmethyl]-1H-indole-5-carboxylate

The title compound was prepared from Intermediate 11 according to MethodJ and was isolated as a brown gum (quantitative) that was used as acrude intermediate. LCMS (ES+) 275.0 (M+H)⁺, RT 2.30 minutes (Method 5).

Intermediate 13 Methyl3-{[(3S)-4-(aminocarbonothioyl)morpholin-3-yl]methyl}-1H-indole-5-carboxylate

The title compound was prepared from Intermediate 12 according to MethodK and was isolated as a yellow solid (99%) after purification by columnchromatography (SiO₂, 0-4% MeOH/DCM). LCMS (ES+) 334.0 (M+H)⁺, RT 2.25minutes (Method 4).

Intermediate 14 Pentafluorophenyl3-{[(3S)-4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-1H-indole-5-carboxylate

To a solution of Intermediate 45 (1.96 g, 4.46 mmol) in DMF (10 mL) andDCM (150 mL) was added pentafluorophenol (0.86 g, 4.68 mmol) and EDC(0.94 g, 4.91 mmol) and the reaction mixture was stirred at r.t. for 16h. DIPEA (1.15 g, 1.56 mL, 8.92 mmol), and further pentafluorophenol(0.22 g, 1.20 mmol) and EDC (0.24 g, 1.25 mmol), were added and stirredfor an additional 2 h at r.t. The reaction mixture was washed with water(2×50 mL), brine (50 mL), dried (Na₂SO₄), filtered and concentrated invacuo. Purification by column chromatography (SiO₂, 0-6% MeOH/DCM) gavethe title compound (1.41 g, 52%) as a brown gum. LCMS (ES+) 607.3(M+H)⁺, RT 3.23 minutes (Method 3).

Intermediate 15 3-Bromo-6,6-dimethylpiperidine-2,4-dione

To a stirred suspension of Intermediate 3 (10.00 g, 70.9 mmol) in THF(200 mL) was added NaHSO₄ (2.12 g, 17.7 mmol). The suspension was cooledto 0° C. and NBS (12.62 g, 70.9 mmol) was added portionwise. Thereaction mixture was stirred at r.t. for 5 h then DCM (200 mL) and water(100 mL) were added. The aqueous fraction was extracted with DCM (2×100mL). The combined organic fractions were washed with water (3×200 mL),dried (Na₂SO₄), filtered and the solvent evaporated in vacuo. The whitesolid was triturated with IPA (3×50 mL), then filtered to give the titlecompound (10.3 g, 66%) as a white solid. δ_(H) (DMSO-d₆) 10.80 (1H, br.s), 7.26 (1H, br. s), 2.50 (2H, s) for the main tautomer. LCMS (ES+)220.0 and 222.0 (1:1 ratio) (M+H)⁺, RT 1.94 minutes (Method 3).

Intermediate 16 N-Benzyl-D-serine

To a stirred solution of D-serine (14.7 g, 140.0 mmol) in aqueous 2MNaOH (70 mL) was added benzaldehyde (14.6 g, 14.0 mL, 138.0 mmol). Thereaction mixture was then stirred at r.t. for 1 h before cooling to 5°C. NaBH₄ (1.5 g, 40.0 mmol) was added portionwise such that an internaltemperature of between 6 and 10° C. was maintained. After addition, thereaction mixture was allowed to stir at 5° C. for 30 minutes and then atr.t. for 1 h. The reaction mixture was cooled to 5° C. and a furtherportion of NaBH₄ (1.5 g, 40.0 mmol) was added portionwise such that aninternal temperature of <10° C. was maintained. The ice bath was removedon completion of addition and the reaction mixture stirred at r.t. for16 h. The reaction mixture was then extracted with Et₂O (3×100 mL) andthe aqueous phase acidified to pH 5 with conc. HCl. The resultant whiteprecipitate was filtered and washed with water. The product was dried invacuo to give the title compound (24.0 g, 88%) as a white solid. δ_(H)(DMSO-d₆) 7.45-7.30 (5H, m), 4.04-3.91 (2H, m), 3.70-3.61 (3H, m), 3.17(1H, t, J 5.8 Hz).

Intermediate 17 (3R)-4-Benzyl-5-oxomorpholine-3-carboxylic acid

To a stirred solution of Intermediate 16 (35.0 g, 179.0 mmol) in aqueousNaOH solution (9.3 g, 200.0 mL, 232.5 mmol) at 0° C. was slowly addedchloroacetyl chloride (24.2 g, 17.0 mL, 214.0 mmol). The reactionmixture was allowed to warm to r.t. and then stirred for 30 minutes.Aqueous 10M NaOH solution (45.0 mL, 465.0 mmol) was added and thereaction mixture heated to 45° C. for 4 h. The reaction mixture was thencooled to 10° C. and acidified to pH 1 with conc. HCl. On standing at 4°C. the product crystallised from the mixture and was collected byfiltration, washed with cold water and then dried in vacuo to give thetitle compound (18.0 g, 43%) as a white solid. δ_(H) (DMSO-d₆)13.51-12.53 (1H, br. s), 7.38-7.25 (5H, m), 5.27 (1H, d, J 15.3 Hz),4.24-4.10 (3H, m), 3.94-3.88 (2H, m), 3.83 (1H, d, J 15.3 Hz). LCMS(ES+) 236.0 (M+H)⁺.

Intermediate 18 [(3S)-(4-Benzylmorpholin-3-0)]methanol

To a stirred solution of Intermediate 17 (17.7 g, 75.3 mmol) in THF (300mL) was added NEt₃ (7.3 g, 10.0 mL, 72.0 mmol). The solution was thencooled to 0° C. and BH₃.Me₂S complex (10M in THF, 45.0 mL, 450.0 mmol)was added slowly. The reaction mixture was heated at reflux for 12 hand, after cooling to r.t., the excess borane was destroyed by slowaddition of MeOH at 0° C. The reaction mixture was concentrated in vacuoand the resultant white solid was dissolved in EtOAc (120 mL) and washedwith aqueous NaOH solution (20% v/v, 2×100 mL). The organic fraction wasthen extracted into aqueous 2M HCl (2×150 mL). The combined acidicaqueous fractions were then basified to pH 14 (addition of solid NaOH)and were re-extracted with EtOAc (2×150 mL). The combined organicfractions were washed with brine (150 mL), dried (MgSO₄), filtered andconcentrated in vacuo to give the title compound (13.5 g, 87%) as aclear oil that required no further purification. δ_(H) (CDCl₃) 7.29-7.16(5H, m), 4.05 (1H, d, J 12.8 Hz), 3.88 (1H, dd, J 11.5 and J 4.5 Hz),3.78 (1H, m), 3.70-3.53 (2H, m), 3.51-3.40 (2H, m), 3.20 (1H, d, J 13.2Hz), 2.68 (1H, dt, J 12.1 and J 2.8 Hz), 2.48 (1H, m), 2.27 (1H, m),2.20-2.15 (1H, br. s).

Intermediate 19 (3S)-Morpholin-3-ylmethanol

To a nitrogen-flushed solution of Intermediate 18 (10.0 g, 48.3 mmol) inMeOH (300 mL) was added 10 wt % palladium on carbon (2.0 g) and thereaction mixture placed in a Parr® apparatus under 50 psi of H₂ for 18h. The resulting mixture was then filtered through Celite® andconcentrated in vacuo to give the title compound (5.2 g, 92%) as acolourless oil. δ_(H) (CDCl₃) 3.81-3.76 (2H, m), 3.58-3.43 (3H, m),3.35-3.28 (1H, m), 2.99-2.91 (5H, br. m). LCMS (ES+) 118.0 (M+H)⁺.

Intermediate 20 2-Iodo-4-difluoromethoxyaniline

A solution of 4-(difluoromethoxy)aniline (1.0 g, 6.30 mmol) in AcOH (6mL) was heated to 60° C. and iodine monochloride (1.07 g, 6.6 mmol) inAcOH (15 mL) was added dropwise. The reaction mixture was then heated to85° C. and stirred for 1.5 h. The reaction mixture was cooled to r.t.and poured into cold water and the resulting suspension filtered. Thefiltrate was concentrated in vacuo to give a dark brown oil.Purification by column chromatography (SiO₂, 10-20% EtOAc/hexanes) gavethe title compound (0.40 g, 22%) as a dark brown oil. δ_(H) (DMSO-d₆)7.38 (1H, d, J 2.7 Hz), 6.98-6.94 (1H, m), 6.97 (1H, t, J 74.8 Hz), 6.75(1H, d, J 8.8 Hz), 5.20 (2H, br. s). LCMS (ES+) 286.0 (M+H)⁺, RT 3.28minutes (Method 5).

Intermediate 21 Methyl3-{[(3S)-4-(tert-butoxycarbonyl)morpholin-3-yl]methyl}-1-methyl-2-(trimethylsilyl)-1H-indole-5-carboxylate

To a stirred solution of Intermediate 11 (2.0 g, 4.48 mmol) in THF (30mL) at 0° C. was added NaH (0.19 g, 60% dispersion in oil, 4.93 mmol).The reaction mixture was stirred at this temperature for 30 minutes.Methyl iodide (0.33 mL, 5.37 mmol) was then added, and the reactionmixture allowed to warm to r.t., then stirred for 18 h. Water (1 mL) wasadded, and the reaction mixture concentrated in vacuo. DCM (25 mL) andwater (10 mL) were added. The organic fraction was separated, washedwith brine (10 mL), dried (Na₂SO₄), filtered and concentrated in vacuo.Purification by column chromatography (SiO₂, 10-25% EtOAc/hexanes) gavethe title compound (1.95 g, 95%) as a pale yellow oil. LCMS (ES+) 405.1((M-^(t)Bu)+H)⁺, RT 3.80 minutes (Method 3).

Intermediate 22 Methyl1-methyl-3[(3S)-morpholin-3-ylmethyl]-1H-indole-5-carboxylate

To a stirred solution of Intermediate 21 (1.95 g, 4.23 mmol) in MeOH (15mL) was added 4M HCl in 1,4-dioxane (20 mL). The reaction mixture wasstirred at r.t. for 16 h, then concentrated in vacuo. Water (10 mL) andDCM (10 mL) were added. The aqueous fraction was separated, basified bythe addition of aqueous sat. NaHCO₃, then extracted with DCM (5×30 mL).The combined organic fractions were dried (Na₂SO₄), filtered andconcentrated in vacuo to give the title compound (1.02 g, 84%) as ayellow solid that was used without further purification. LCMS (ES+)289.2 (M+H)⁺, RT 2.00 minutes (Method 3).

Intermediate 23 Methyl3-{[(3S)-4-(aminocarbonothioyl)morpholin-3-yl]methyl}-1-methyl-1H-indole-5-carboxylate

The title compound was prepared from Intermediate 22 according to MethodK and was isolated as a brown gum (80%) after purification by columnchromatography (SiO₂, 0-6% MeOH/DCM). LCMS (ES+) 348.2 (M+H)⁺, RT 2.63minutes (Method 3).

Intermediate 24 Pentafluorophenyl3-{[(3S)-4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-1-methyl-1H-indole-5-carboxylate

To a stirred solution of Example 2 (1.0 g, 2.20 mmol) in DMF (20 mL) wasadded pentafluorophenol (0.49 g, 2.64 mmol), DIPEA (0.77 mL, 4.41 mmol)and EDC (0.55 g, 2.86 mmol). The reaction mixture was stirred at r.t.for 16 h, then concentrated in vacuo. DCM (15 mL) and water (15 mL) wereadded. The organic fraction was separated, dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification by column chromatography (SiO₂, 0-4%MeOH/DCM) gave the title compound (1.04 g, 76%) as a yellow gum. LCMS(ES+) 621.3 (M+H)⁺, RT 3.52 minutes (Method 4).

Intermediate 25 tert-Butyl(3S)-3-{[5-cyano-2-(trimethylsilyl)-1H-indol-3-yl]methyl}morpholine-4-carboxylate

The title compound was prepared from Intermediate 7 and4-amino-3-iodobenzonitrile according to Method I and was isolated as ayellow solid (50%) after work-up (EtOAc and water) and purification bycolumn chromatography (SiO₂, 5-100% EtOAc/hexanes). LCMS (ES+) 414.0(M+H)⁺, RT 3.92 minutes (Method 5).

Intermediates 26 and 27(3S)-3-[3-(Trimethylsilyl)prop-2-yn-1-yl]morpholine-4-carbothioamide and(3S)-3-(Prop-2-yn-1-yl)morpholine-4-carbothioamide respectively

To a stirred solution of trimethylsilyl acetylene (30.3 mL, 215.0 mmol)in THF (300 mL) at 0° C. was added n-butyllithium (86.2 mL, 2.5M inhexanes, 215.0 mmol) dropwise over 15 minutes. After stirring at thistemperature for 30 minutes, Intermediate 4 (19.3 g, 107.7 mmol) wasadded over 5 minutes. The reaction mixture was stirred at 0° C. for 20minutes, and then allowed to warm to r.t. After stirring at r.t. for 40minutes, the reaction mixture was quenched by the addition of 2M aqueousHCl (80 mL) and MeOH (50 mL), then stirred at r.t. for 3 h. The reactionmixture was concentrated in vacuo. The residue was dissolved in THF (60mL). DIPEA (4.9 mL, 28.4 mmol) then 1,1′-thiocarbonyldiimidazole (5.3 g,29.7 mmol) were added. The reaction mixture was stirred at r.t. for 16h, then partitioned between DCM (50 mL) and water (30 mL). The organicfraction was dried (Na₂SO₄), filtered and concentrated in vacuo.Purification by column chromatography (SiO₂, 0-2% MeOH/DCM, followed bySiO₂, 60-80% EtOAc/hexanes) gave the first title compound (2.35 g, 34%)as a brown gum, LCMS (ES+) 257.0 (M+H)⁺, RT 3.206 minutes (Method 5),followed by the second title compound (1.55 g, 31%) as a brown gum, LCMS(ES+) 185.0 (M+H)⁺, RT 2.47 minutes (Method 5). They were both usedindividually without further purification.

Intermediate 28 Methyl3-{[(3S)-4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-2-(trimethylsilyl)-1-benzofuran-5-carboxylate

The title compound was prepared from Intermediate 49 and methyl4-hydroxy-3-iodobenzoate according to Method I and was isolated as abrown gum (49%) after purification by column chromatography (SiO₂,60-100% EtOAc/hexanes). LCMS (ES+) 528.2 (M+H)⁺, RT 3.46 minutes (Method9).

Intermediate 293-{[(3S)-4-(6,6-Dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-1-benzofuran-5-carboxylicacid

To a stirred solution of Intermediate 28 (0.326 g, 0.62 mmol) in1,4-dioxane (8 mL) was added a solution of LiOH.H₂O (0.054 g, 1.29 mmol)in water (5 mL). The reaction mixture was stirred at r.t. for 1 h, thenat 60° C. for 1 h, and then at r.t. for 18 h before being concentratedin vacuo. The residue was dissolved in water (20 mL) and the solutionwashed with DCM (3×25 mL). The aqueous fraction was separated, acidifiedwith 1M aqueous HCl, then extracted with EtOAc (4×50 mL). The combinedorganic fractions were dried (Na₂SO₄), filtered and concentrated invacuo to give the title compound (0.135 g, 49%) as an off-white solidthat was used without further purification. LCMS (ES+) 442.2 (M+H)⁺, RT1.82 minutes (Method 9).

Intermediate 30 Pentafluorophenyl3-{[(3S)-4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-e]pyridin-2-yl)morpholin-3-yl]methyl}-1-benzofuran-5-carboxylate

To a stirred solution of Intermediate 29 (0.135 g, 0.31 mmol) in DMF (8mL) was added pentafluorophenol (0.062 g, 0.34 mmol) and EDC (0.070 g,0.37 mmol). The reaction mixture was stirred at r.t. for 16 h, then usedas such for the next step. LCMS (ES+) 608.1 (M+H)⁺, RT 3.39 minutes(Method 9).

Intermediate 31 tert-Butyl(3S)-3-{[5-cyano-1-methyl-2-(trimethylsilyl)-1H-indol-3-yl]methyl}morpholine-4-carboxylate

To a stirred solution of Intermediate 25 (1.6 g, 3.87 mmol) in THF (20mL) at −78° C. was added n-butyllithium (1.9 mL, 2.5M in THF, 4.85mmol). After stirring at this temperature for 10 minutes, MeI (0.3 mL,4.84 mmol) was added, and the reaction mixture warmed to r.t. over 1 h.EtOAc (10 mL) and brine (20 mL) were added. The aqueous fraction wasseparated and extracted with EtOAc (3×20 mL). The combined organicfractions were dried (Na₂SO₄), filtered and evaporated in vacuo.Purification by column chromatography (SiO₂, 15-60% EtOAc/hexanes) gavethe title compound (1.60 g, quantitative) as an off-white solid. LCMS(ES+) 427.0 (M+H)⁺, RT 2.51 minutes (Method 12).

Intermediate 321-Methyl-3-[(3S)-morpholin-3-ylmethyl]-1H-indole-5-carbonitrile

The title compound was prepared from Intermediate 31 according to MethodJ and was isolated as a yellow oil (71%) that was used without furtherpurification. LC, RT 1.45 minutes (Method 12).

Intermediate 33(3S)-3-[(5-Cyano-1-methyl-1H-indol-3-yl)methyl]morpholine-4-carbothioamide

The title compound was prepared from Intermediate 32 according to MethodK and was isolated as a brown solid (92%) that was used without furtherpurification. LCMS (ES+) 298.0 (M-NH₂)⁺, RT 1.76 minutes (Method 12).

Intermediate 34 tert-Butyl(3S)-3-{[2-(trimethylsilyl)-1H-indol-3-yl]methyl}morpholine-4-carboxylate

The title compound was prepared from Intermediate 7 and 2-iodoanilineaccording to Method I and was isolated as a white solid (40%) afterpurification by column chromatography (SiO₂, 15-60% EtOAc/hexanes). LCMS(ES+) 333.0 ((M-^(t)Bu)+H)⁺, 2.50 minutes (Method 12).

Intermediate 35 tert-Butyl(3S)-3-{[1-methyl-2-(trimethylsilyl)-1H-indol-3-yl]methyl}morpholine-4-carboxylate

The title compound was prepared from Intermediate 34 according to MethodW (using only 1.1 equivalent of NaH, doing the work-up in EtOAc andwater, and drying the separated organic fraction with Na₂SO₄) and wasisolated as a yellow oil (24%) after purification by columnchromatography (SiO₂, 15-60% EtOAc/hexanes). δ_(H) (DMSO-d₆) 7.90-7.60(1H, br. s), 7.39 (1H, d, J 8.3 Hz), 7.25-7.10 (1H, m), 7.10-7.00 (1H,m), 4.07-4.05 (1H, m), 3.88-3.85 (1H, m), 3.80 (3H, s), 3.70-3.60 (1H,br. s), 3.48-3.39 (2H, m), 3.31-3.24 (1H, m), 3.24-3.22 (2H, m),2.90-2.75 (1H, m), 1.38 (9H, s), 0.47 (9H, s). LCMS (ES+) 403.0 (M+H)⁺,347.0 ((M-^(t)Bu)+H), RT 2.66 minutes (Method 12).

Intermediate 36 1-Methyl-3-[(3S)-morpholin-3-ylmethyl]-1H-indole

The title compound was prepared from Intermediate 35 according to MethodJ and was isolated as a colourless oil (88%) that was used withoutfurther purification. LCMS (ES+) 230.0 (M+H)⁺, RT 1.53 minutes (Method12).

Intermediate 37(3S)-3-[(1-Methyl-1H-indol-3-yl)methyl]morpholine-4-carbothioamide

The title compound was prepared from Intermediate 36 according to MethodK and was isolated as a yellow solid (48%) that was used without furtherpurification. LCMS (ES+) 290.0 (M+H)⁺, RT 1.66 minutes (Method 12).

Intermediate 386,6-Dimethyl-2-[(3S)-3-{[2-(trimethylsilyl)-1-benzofuran-3-yl]methyl}morpholin-4-yl]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5H)-one

The title compound was prepared from Intermediate 49 and 2-iodophenolaccording to Method I and was isolated as a yellow oil (77%) afterpurification by column chromatography (SiO₂, 0-50% EtOAc/hexanes). δ_(H)(CDCl₃) 7.84-7.81 (1H, m), 7.27-7.25 (1H, m), 7.11-7.07 (2H, m),5.00-4.90 (1H, m), 4.30-4.20 (1H, m), 4.00-3.86 (1H, m), 3.60-3.20 (7H,m), 1.41 (2H, s), 1.98-1.20 (6H, m), 0.22 (9H, s).

Intermediate 39 4-Hydroxy-3-iodobenzaldehyde

To a stirred solution of 4-hydroxybenzaldehyde (2.0 g, 16.39 mmol) inAcOH (30 mL) was added N-iodosuccinimide (4.5 g, 19.67 mmol). Thereaction mixture was stirred at r.t. for 16 h, then filtered. Thefiltrate was poured onto water (100 mL) and EtOAc (50 mL) was added. Theaqueous fraction was separated, then extracted with EtOAc (3×50 mL). Thecombined organic fractions were washed with water (2×20 mL), dried(Na₂SO₄), filtered and concentrated in vacuo to give the title compound(2.0 g, 50%) as a white solid that was used without furtherpurification. LCMS (ES−) 247.1 (M−H)⁻, RT 1.44 minutes (Method 9).

Intermediate 40 4-Hydroxy-3-iodobenzonitrile

To a stirred solution of Intermediate 39 (5.2 g, 20.97 mmol) in formicacid (60 mL) was added sodium acetate (2.1 g, 25.16 mmol), followed byhydroxylamine hydrochloride (8.7 g, 125.8 mmol). The reaction mixturewas stirred at 105° C. for 3 h, then cooled to r.t. and poured ontowater. The solid formed was filtered to give the title compound (3.0 g,58%) as a white solid that was used without further purification. LCMS(ES+) 246.1 (M+H)⁺, RT 1.64 minutes (Method 11).

Intermediate 413-[(3S)-Morpholin-3-ylmethyl]-1-benzofuran-5-carbonitrile

The title compound was prepared from Intermediate 7 and Intermediate 40according to Method I, followed by Method J then Method AI, and wasisolated as a yellow solid (10%) after purification by columnchromatography (SiO₂, 0-10% MeOH/DCM). LCMS (ES+) 243.1 (M+H)⁺, RT 1.41minutes (Method 12).

Intermediate 42(3S)-3-[(5-Cyano-1-benzofuran-3-yl)methyl]morpholine-4-carbothioamide

The title compound was prepared from Intermediate 41 according to MethodK and was isolated as a yellow solid (quantitative) that was usedwithout further purification. LCMS (ES+) 302.1 (M+H⁺), RT 1.54 minutes(Method 12).

Intermediate 43 (Method N)2-[(3S)-3-{[5-(Difluoromethoxy)-1H-indol-3-yl]methyl}morpholin-4-yl]-6,6-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-e]pyridin-4(5H)-one

To a solution of Intermediate 10 (0.07 g, 0.21 mmol) in THF (3 mL) wasadded Intermediate 15 (0.048 g, 0.22 mmol) and DIPEA (0.059 mL, 0.41mmol) and the reaction mixture was stirred at 60° C. for 1.5 h. Thereaction mixture was concentrated in vacuo to give a yellow oil.Purification by column chromatography (SiO₂, 1-2% MeOH/DCM; followed bySiO₂, 80-100% EtOAc/DCM) and freeze-drying (MeCN/water) gave the titlecompound (0.019 g, 20%) as an off-white solid. δ_(H) (CD₃OD) 7.73 (1H,d, J 2.1 Hz), 7.32 (1H, d, J 8.7 Hz), 7.20 (1H, s), 6.93 (1H, dd, J 8.7and J 2.3 Hz), 6.72 (1H, t, J 75.6 Hz), 4.38-4.30 (1H, m), 4.09-4.06(1H, m), 3.90 (1H, d, J 11.8 Hz), 3.71-3.46 (4H, m), 3.40-3.31 (1H, m),3.10-3.04 (1H, m), 2.83 (2H, s), 1.36 (6H, s). Exchangeable protons werenot observed. LCMS (ES+) 463.0 (M+H)⁺, RT 3.07 minutes (Method 5).

Intermediate 44 Methyl3-{[(3S)-4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-e]pyridin-2-yl)morpholin-3-yl]methyl}-1H-indole-5-carboxylate

The title compound was prepared from Intermediate 13 and Intermediate 15according to Method N and was isolated as a yellow solid (69%) afterpurification by column chromatography (SiO₂, 0-5% MeOH/DCM). δ_(H)(CD₃OD) 8.62 (1H, d, J 1.0 Hz), 7.81 (1H, dd, J 8.6 and J 1.6 Hz), 7.39(1H, d, J 8.6 Hz), 7.24 (1H, s), 4.37 (1H, m), 4.07 (1H, m), 3.95 (3H,s), 3.90 (1H, d, J 11.7 Hz), 3.73-3.52 (4H, m), 3.38 (1H, m), 3.18 (1H,dd, J 13.9 and J 5.4 Hz), 2.87 (1H, d, J 16.9 Hz), 2.81 (1H, d, J 16.9Hz), 1.37 (3H, s), 1.36 (3H, s). Exchangeable protons were not observed.LCMS (ES+) 455.0 (M+H)⁺, RT 2.59 minutes (Method 4).

Intermediate 453-{[(3S)-4-(6,6-Dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-1H-indole-5-carboxylicacid

To Intermediate 44 (2.18 g, 4.80 mmol) dissolved in 1,4-dioxane (20 mL)was added a solution of LiOH.H₂O (0.40 g, 9.60 mmol) in water (20 mL)and the reaction mixture stirred at r.t. for 16 h. Further LiOH.H₂O(0.10 g, 2.40 mmol) in water (5 mL) was added and the reaction mixturestirred at 50° C. for 3 h. The reaction mixture was concentrated invacuo and the crude residue was partitioned between water (100 mL) andDCM (200 mL). The aqueous phase was acidified to pH 1 by the addition ofaqueous HCl (10% v/v) and extracted with EtOAc (3×200 mL) and thecombined organic fractions were concentrated in vacuo to give the titlecompound (2.37 g, quantitative) as a yellow solid. δ_(H) (DMSO-d₆) 12.35(1H, br. s), 11.23 (1H, s), 8.58 (1H, s), 7.71 (1H, dd, J 8.6 and J 1.5Hz), 7.38 (1H, d, J 8.6 Hz), 7.30 (1H, d, J 2.1 Hz), 7.27 (1H, s), 4.27(1H, m), 3.98 (1H, m), 3.73 (1H, d, J 11.6 Hz), 3.62-3.43 (4H, m), 3.28(1H, m), 2.96 (1H, dd, J 13.9 and J 3.9 Hz), 2.83 (1H, d, J 16.9 Hz),2.76 (1H, d, J 16.9 Hz), 1.26 (6H, s). LCMS (ES+) 441.0 (M+H)⁺, RT 2.65minutes (Method 5).

Intermediate 46 (Method O)6,6-Dimethyl-2-[(3S)-3-{[5-(piperidin-1-ylcarbonyl)-1H-indol-3-yl]methyl}morpholin-4-yl]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5H)-one

To Intermediate 14 (0.206 g, 0.34 mmol) dissolved in DCM (5 mL) wasadded piperidine (0.035 g, 0.04 mL, 0.409 mmol) and the reaction mixturestirred at r.t. for 1 h. The reaction mixture was concentrated in vacuoand the crude residue was purified by column chromatography (SiO₂, 0-5%MeOH/DCM). The sample was freeze-dried (MeCN/water) to give the titlecompound (0.086 g, 50%) as a white powder. δ_(H) (DMSO-d₆) 11.07 (1H,s), 7.91 (1H, s), 7.36 (1H, d, J 8.3 Hz), 7.29 (1H, s), 7.27 (1H, d, J1.9 Hz), 7.10 (1H, dd, J 8.5 and J 1.3 Hz), 4.19 (1H, m), 3.98 (1H, d, J6.0 Hz), 3.74 (1H, d, J 11.7 Hz), 3.57 (4H, br. s), 3.50 (4H, m),3.36-3.22 (1H, m), 2.92 (1H, dd, J 13.9 and J 4.1 Hz), 2.71 (2H, t, J17.1 Hz), 1.66-1.49 (6H, m), 1.26 (6H, s). LCMS (ES+) 508.0 (M+H)⁺, RT2.88 minutes (Method 5).

Intermediate 473-{[(3.5)-4-(6,6-Dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-N,N-dimethyl-1H-indole-5-carboxamide

The title compound was prepared from Intermediate 14 and dimethylamineaccording to Method O and was isolated as a white powder (70%) afterpurification by column chromatography (SiO₂, 0-10% MeOH/DCM) andfreeze-drying (MeCN/water). δ_(H) (CD₃OD) 8.08 (1H, d, J 0.9 Hz), 7.41(1H, dd, J 8.3 and J 0.6 Hz), 7.24 (1H, s), 7.21 (1H, dd, J 8.5 and J1.7 Hz), 4.35 (1H, m), 4.07 (1H, m), 3.89 (1H, d, J 11.7 Hz), 3.76-3.54(4H, m), 3.42 (1H, dd, J 13.9 and J 10.2 Hz), 3.18-3.05 (7H, m), 2.82(2H, s), 1.38 (6H, s). Exchangeable protons were not observed. LCMS(ES+) 468.5 (M+H)⁺, RT 2.36 minutes (Method 3).

Intermediate 48 (Method W)N,N,1-Trimethyl-3-{[(3S)-4-(5,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-1H-indole-5-carboxamide

To a stirred solution of Intermediate 47 (0.103 g, 0.22 mmol) in DMF (5mL) was added NaH (0.019 g, 60% dispersion in oil, 0.48 mmol) and thereaction mixture was stirred at r.t. for 10 minutes. Methyl iodide (0.34mL, 0.55 mmol) was added. The reaction mixture was stirred at r.t. for 2h, then quenched with the addition of water (0.5 mL) and concentrated invacuo. DCM (20 mL) and water (20 mL) were added. The organic fractionwas separated via an Isolute® phase separation cartridge andconcentrated in vacuo. Purification by column chromatography (SiO₂, 0-3%MeOH/DCM) gave the title compound (0.085 g, 78%) as a white solid. δ_(H)(CD₃OD) 8.08 (1H, d, J 0.9 Hz), 7.41 (1H, d, J 8.5 Hz), 7.27 (1H, dd, J8.5 and 1.5 Hz), 7.18 (1H, s), 4.38-4.27 (1H, m), 4.13-4.00 (1H, m),3.88 (1H, d, J 11.8 Hz), 3.80 (3H, s), 3.73-3.52 (4H, m), 3.46-3.34 (1H,m), 3.23-3.02 (7H, m), 2.99 (3H, s), 2.87 (2H, s), 1.40 (3H, s), 1.39(3H, s). LCMS (ES+) 496.3 (M+H)⁺, RT 2.45 minutes (Method 3).

Intermediate 496,6-Dimethyl-2-{(3S)-3-[3-(trimethylsilyl)prop-2-yn-1-yl]morpholin-4-yl}-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5H)-one

The title compound was prepared from Intermediate 15 and Intermediate 26according to Method N and was isolated as a yellow solid (70%) afterpurification by column chromatography (SiO₂, 60-80% EtOAc/hexanes). Aportion (0.10 g) of this material was further purified by columnchromatography (SiO₂, 0-2% MeOH/DCM) to give the title compound (0.06 g)as a white solid. δ_(H) (CD₃OD) 4.22-4.08 (1H, m), 4.02-3.83 (2H, m),3.71-3.50 (3H, m), 3.49-3.33 (1H, m), 2.76-2.66 (4H, m), 1.29 (3H, s),1.28 (3H, s), 0.00 (9H, s). Exchangeable proton was not observed. LCMS(ES+) 378.2 (M+H)⁺, RT 2.86 minutes (Method 4).

Example 1 Methyl3-{[(3S)-4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-1-methyl-1H-indole-5-carboxylate

The title compound was prepared from Intermediate 23 and Intermediate 15according to Method N and was isolated as a white solid (91%) afterpurification by column chromatography (SiO₂, 0-4% MeOH/DCM, followed bySiO₂, 0-2% MeOH/EtOAc), then preparative HPLC (Method 13). δ_(H) (CD₃OD)8.62-8.59 (1H, m), 7.86 (1H, dd, J 8.7 and 1.6 Hz), 7.41-7.35 (1H, m),7.18 (1H, s), 4.41-4.31 (1H, m), 4.13-4.02 (1H, m), 3.95 (3H, s), 3.90(1H, d, J 11.8 Hz), 3.79 (3H, s), 3.76-3.55 (4H, m), 3.44-3.36 (1H, m),3.15 (1H, dd, J 13.9 and 5.4 Hz), 2.85 (1H, d, J 16.9 Hz), 2.80 (1H, d,J 16.9 Hz), 1.36 (3H, s), 1.35 (3H, s). Exchangeable proton was notobserved. LCMS (ES+) 469.3 (M+H)⁺, RT 2.88 minutes (Method 4).

Example 23-{[(3S)-4-(6,6-Dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-1-methyl-1H-indole-5-carboxylicacid

To a stirred suspension of Example 1 (1.15 g, 2.46 mmol) in 1,4-dioxane(20 mL) and MeOH (5 mL) was added a solution of LiOH.H₂O (0.21 g, 4.91mmol) in water (5 mL). The reaction mixture was stirred at 60° C. for 16h, then concentrated in vacuo. Water (100 mL) and DCM (200 mL) wereadded. The aqueous fraction was separated, acidified to pH 1 by theaddition of 1M aqueous HCl, then extracted with EtOAc (4×200 mL). Thecombined organic fractions were dried (Na₂SO₄), filtered andconcentrated in vacuo. The solid was washed with EtOAc to give the titlecompound (1.0 g, 90%) as a white solid. δ_(H) (CD₃OD) 8.64 (1H, d, J 1.1Hz), 7.88 (1H, dd, J 8.7 and 1.5 Hz), 7.36 (1H, d, J 8.7 Hz), 7.15 (1H,s), 4.52-4.39 (1H, m), 4.12-4.02 (1H, m), 3.91 (1H, d, J 11.7 Hz), 3.79(3H, s), 3.76-3.65 (2H, m), 3.64-3.50 (2H, m), 3.44-3.34 (1H, m), 3.16(1H, dd, J 13.9 and 5.3 Hz), 2.87 (1H, d, J 17.0 Hz), 2.81 (1H, d, J17.0 Hz), 1.36 (3H, s), 1.35 (3H, s). Exchangeable protons were notobserved. LCMS (ES+) 455.2 (M+H)⁺, RT 2.57 minutes (Method 3).

Example 33-{[(3S)-4-(6,6-Dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-morpholin-3-yl]methyl}-N,1-dimethyl-N-(2-methoxyethyl)-1H-indole-5-carboxamide

The title compound was prepared from Intermediate 24 andN-(2-methoxyethyl)-methylamine according to Method O and was isolated asa white solid (70%) after purification by column chromatography (SiO₂,0-6% MeOH/DCM). δ_(H) (CD₃OD) 8.09 (1H, br. s), 7.40 (1H, d, J 8.4 Hz),7.26 (1H, dd, J 8.4 and 1.4 Hz), 7.17 (1H, s), 4.42-4.32 (1H, m),4.13-4.02 (1H, m), 3.89 (1H, d, J 11.7 Hz), 3.79 (3H, s), 3.74-3.25(12H, m), 3.16 (3H, s), 3.14-3.04 (1H, m), 2.81 (2H, s), 1.37 (6H, s).Exchangeable proton was not observed. LCMS (ES+) 526.3 (M+H)⁺, RT 2.58minutes (Method 3).

Example 4N-(Cyanomethyl)-3-{[(3S)-4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-N,1-dimethyl-1H-indole-5-carboxamide

The title compound was prepared from Intermediate 24 and(methylamino)-acetonitrile hydrochloride according to Method O (with theaddition of 1.2 equivalents of DIPEA) and was isolated as a white solid(63%) after purification by column chromatography (SiO₂, 0-6% MeOH/DCM).δ_(H) (CD₃OD) 8.17 (1H, d, J 0.9 Hz), 7.44 (1H, d, J 8.6 Hz), 7.34 (1H,dd, J 8.6 and 1.5 Hz), 7.20 (1H, s), 4.59 (1H, d, J 17.3 Hz), 4.51 (1H,d, J 17.3 Hz), 4.41-4.30 (1H, m), 4.11-4.01 (1H, m), 3.88 (1H, d, J 11.7Hz), 3.80 (3H, s), 3.75-3.50 (4H, m), 3.45-3.33 (1H, m), 3.24 (3H, s),3.11 (1H, dd, J 13.9 and 4.9 Hz), 2.81 (2H, s), 1.37 (3H, s), 1.36 (3H,s). Exchangeable proton was not observed. LCMS (ES+) 507.2 (M+H)⁺, RT2.62 minutes (Method 3).

Example 52-[(3S)-3-{[5-(Azetidin-1-ylcarbonyl)-1-methyl-1H-indol-3-yl]methyl}morpholin-4-yl]-6,6-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5H)-one

The title compound was prepared from Intermediate 24 and azetidinehydrochloride according to Method O (with the addition of 1.2equivalents of DIPEA) and was isolated as a white solid (65%) afterpurification by column chromatography (SiO₂, 0-6% MeOH/DCM). δ_(H)(CD₃OD) 8.19 (1H, d, J 1.0 Hz), 7.50 (1H, dd, J 8.6 and 1.6 Hz), 7.40(1H, d, J 8.6 Hz), 7.18 (1H, s), 4.53-4.45 (2H, m), 4.36-4.28 (1H, m),4.29-4.18 (2H, m), 4.11-4.01 (1H, m), 3.87 (1H, d, J 11.8 Hz), 3.79 (3H,s), 3.74-3.55 (4H, m), 3.39 (1H, dd, J 13.9 and 10.2 Hz), 3.10 (1H, dd,J 13.9 and 4.9 Hz), 2.84 (2H, s), 2.44-2.35 (2H, m), 1.38 (3H, s), 1.37(3H, s). Exchangeable proton was not observed. LCMS (ES+) 494.3 (M+H)⁺,RT 2.59 minutes (Method 3).

Example 63-{[(3S)-4-(6,6-Dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-d]pyridin-2-yl)morpholin-3-yl]methyl}-N,N,1-trimethyl-1H-indole-5-carboxamide

The title compound was prepared from Intermediate 24 and dimethylamine(40% v/v in water) according to Method O (in MeCN) and was isolated as awhite solid (92%) after purification by column chromatography (SiO₂,0-6% MeOH/DCM). δ_(H) (CD₃OD) 8.07 (1H, d, J 1.0 Hz), 7.41 (1H, d, J 8.5Hz), 7.27 (1H, dd, J 8.5 and 1.6 Hz), 7.18 (1H, s), 4.39-4.29 (1H, m),4.13-4.01 (1H, m), 3.88 (1H, d, J 11.7 Hz), 3.79 (3H, s), 3.75-3.55 (4H,m), 3.39 (1H, dd, J 13.9 and 10.1 Hz), 3.14 (6H, br. s), 3.12-3.02 (1H,m), 2.80 (2H, s), 1.37 (6H, s). Exchangeable proton was not observed.LCMS (ES+) 482.3 (M+H)⁺, RT 2.57 minutes (Method 3).

Example 7 Methyl3-{[(3S)-4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-1-benzofuran-5-carboxylate

The title compound was prepared from Intermediate 28 (dissolved in MeOH)according to Method J and was isolated as a white solid (44%) afterpurification by column chromatography (SiO₂, 60-100% EtOAc/hexanes).δ_(H) (CD₃OD) 8.59 (1H, d, J 1.4 Hz), 7.93 (1H, dd, J 8.7 and 1.7 Hz),7.69 (1H, s), 7.44 (1H, dd, J 8.7 and 0.4 Hz), 4.55-4.39 (1H, m),4.05-3.94 (1H, m), 3.89 (3H, s), 3.82 (1H, d, J 11.9 Hz), 3.70-3.40 (4H,m), 3.35-3.24 (1H, m), 3.08 (1H, dd, J 14.1 and 5.8 Hz), 2.77 (1H, d, J17.0 Hz), 2.70 (1H, d, J 17.0 Hz), 1.28 (3H, s), 1.25 (3H, s).Exchangeable proton was not observed. LCMS (ES+) 456.1 (M+H)⁺, RT 2.68minutes (Method 9).

Example 83-{[(3S)-4-(6,6-Dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-N,N-dimethyl-1-benzofuran-5-carboxamide

The title compound was prepared from Intermediate 30 and dimethylamine(40% v/v in water, 3 mL) according to Method O and was isolated as awhite solid (33% from Intermediate 29) after purification by columnchromatography (SiO₂, 0-4% MeOH/DCM). δ_(H) (CD₃OD) 8.16 (1H, d, J 1.3Hz), 7.76 (1H, s), 7.54 (1H, dd, J 8.5 and 0.4 Hz), 7.39 (1H, dd, J 8.5and 1.7 Hz), 4.55-4.45 (1H, m), 4.14-4.01 (1H, m), 3.90 (1H, d, J 11.9Hz), 3.79-3.59 (3H, m), 3.59-3.49 (1H, m), 3.45-3.34 (1H, m), 3.24-3.00(7H, m), 2.81 (1H, d, J 16.9 Hz), 2.75 (1H, d, J 16.9 Hz), 1.37 (3H, s),1.35 (3H, s). Exchangeable proton was not observed. LCMS (ES+) 469.1(M+H)⁺, RT 1.95 minutes (Method 9), RT 1.50 minutes (Method 10).

Example 92-[(3S)-3-{[5-(Azetidin-1-ylcarbonyl)-1-benzofuran-3-yl]methyl}morpholin-4-yl]-6,6-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5H)-one

The title compound was prepared from Intermediate 30 and azetidinehydrochloride (40% v/v in water, 3 mL) according to Method O (with theaddition of 1.2 equivalents of DIPEA) and was isolated as a white solid(28% from Intermediate 29) after purification by column chromatography(SiO₂, 0-4% MeOH/DCM, followed by SiO₂, 0-5% MeOH/EtOAc). δ_(H) (CD₃OD)8.27 (1H, d, J 1.3 Hz), 7.77 (1H, s), 7.61 (1H, dd, J 8.6 and 1.7 Hz),7.53 (1H, d, J 8.6 Hz), 4.53-4.45 (3H, m), 4.36-4.28 (2H, m), 4.15-4.02(1H, m), 3.89 (1H, d, J 11.9 Hz), 3.77-3.54 (4H, m), 3.37 (1H, m), 3.12(1H, dd, J 14.0 and 5.4 Hz), 2.85 (1H, d, J 16.8 Hz), 2.79 (1H, d, J16.8 Hz), 2.44-2.35 (2H, m) 1.37 (3H, s), 1.35 (3H, s). Exchangeableproton was not observed. LCMS (ES+) 481.1 (M+H)⁺, RT 1.89 minutes(Method 9).

Example 103-{[(3S)-4-(6,6-Dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-1-methyl-1H-indole-5-carbonitrile

The title compound was prepared from Intermediate 15 and Intermediate 33according to Method N and was isolated as a white solid (38%) afterpurification by column chromatography (SiO₂, 0-10% MeOH/EtOAc), followedby preparative HPLC (Method 13). δ_(H) (DMSO-d₆) 8.45 (1H s), 7.64-7.56(1H, m), 7.50 (1H, dd, J 8.6 and 1.3 Hz), 7.43 (1H, s), 7.35-7.32 (1H,m), 4.29-4.21 (1H, m), 4.02-3.97 (1H, m), 3.78 (3H, s), 3.74 (1H, d, J11.9 Hz), 3.60-3.45 (4H, m), 3.32-3.24 (1H, m), 2.93 (1H, dd, J 14.1 and11.8 Hz), 2.77 (2H, s), 1.26 (6H, s). LCMS (ES+) 436.2 (M+H)⁺, RT 2.37minutes (Method 12).

Example 113-{[(3S)-4-(6,6-Dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-1-methyl-1H-indole

The title compound was prepared from Intermediate 15 and Intermediate 37according to Method N and was isolated as a white solid (39%) afterpurification by preparative HPLC (Method 13). δ_(H) (DMSO-d₆) 7.77 (1H,d, J 8.8 Hz), 7.39 (1H, d, J 8.1 Hz), 7.32 (1H, s), 7.20 (1H, s),7.23-7.10 (1H, m), 7.06 (1H, s), 4.06-3.99 (1H, m), 4.10-3.85 (1H, m),3.72 (3H, s), 3.70-3.60 (1H, m), 3.56-3.54 (2H, m), 3.49-3.47 (1H, m),3.33-3.31 (2H, m), 2.85 (1H, dd, J 13.8 and 4.0 Hz), 2.73 (2H, d, J 3.2Hz), 1.26 (6H, s). LCMS (ES+) 411.2 (M+H)⁺, RT 2.49 minutes (Method 12).

Example 12 (Method AI)2-[(3S)-3-(1-Benzofuran-3-ylmethyl)morpholin-4-yl]-6,6-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5H)-one

To a stirred solution of Intermediate 38 (0.25 g, 0.53 mmol) in1,4-dioxane (4 mL) was added a solution of lithium hydroxide monohydrate(0.047 g, 1.11 mmol) in water (2 mL). The reaction mixture was stirredat 60° C. for 2 h. EtOAc (20 mL) was added. The organic fraction wasseparated, washed with water (3×5 mL), dried (MgSO₄), filtered andconcentrated in vacuo. Purification by column chromatography (SiO₂,EtOAc), followed by preparative HPLC (Method 13), gave the titlecompound (0.050 g, 24%) as a white solid. δ_(H) (CDCl₃) 7.92-7.90 (1H,m), 7.56 (1H, s), 7.51-7.50 (1H, m), 7.36-7.30 (2H, m), 5.17 (1H, s),4.30-4.28 (1H, m), 4.09-4.07 (1H, m), 3.90-3.87 (1H, m), 3.74-3.57 (4H,m), 3.42-3.36 (1H, m), 3.03-2.98 (1H, m), 2.87-2.86 (2H, m), 1.41 (6H,m). LCMS (ES+) 398.2 (M+H)⁺, RT 2.50 minutes (Method 12).

Example 133-{[(3S)-4-(6,6-Dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-e]pyridin-2-yl)morpholin-3-yl]methyl}-1-benzofuran-5-carbonitrile

The title compound was prepared from Intermediate 15 and Intermediate 42according to Method N and was isolated as a white solid (15%) afterpurification by preparative HPLC (Method 13). δ_(H) (CDCl₃) 8.65 (1H,s), 7.66-7.55 (3H, m), 5.27 (1H, s), 4.52-4.40 (1H, d, J 10.6 Hz),4.11-4.08 (1H, d, J 11.3 Hz), 3.90-3.50 (4H, m), 3.43-3.30 (2H, m), 3.02(2H, s), 3.00-2.90 (1H, d, J 13.7 Hz), 1.44 (6H, s). LCMS (ES+) 423.3(M+H)⁺, RT 2.32 minutes (Method 12).

The invention claimed is:
 1. A method for the treatment of anoncological condition for which the administration of a selective PI3Kinhibitor is indicated which comprises administering to a patient inneed of such treatment an effective amount of3-{[(3S)-4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)morpholin-3-yl]methyl}-N,N,1-trimethyl-1H-indole-5-carboxamide,or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1wherein said oncological condition is leukemia.
 3. The method of claim 1wherein said oncological condition is glioblastoma.
 4. The method ofclaim 1 wherein said oncological condition is lymphoma.
 5. The method ofclaim 1 wherein said oncological condition is melanoma.
 6. The method ofclaim 1 wherein said oncological condition is a human cancer selectedfrom the group consisting of cancers of the liver, bone, skin, brain,pancreas, lung, breast, stomach, colon, rectum, prostate, ovary, andcervix.